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Making LSD In The Laboratory
----------------------------
        To make synthetic acid, you need a basic understanding of chemistry
and access to a lab. Since I don't quite understand all the chemical hocus-
pocus, I'm going to cop out and quote you the patent for it. If you don't
understand chemistry, just skip this recipe and go on to the next one for
acid, it's much simpler.

Preparation for Lysergic Acid Amides:
United States Patent Office                                          2,736,728
                        Patented February 28, 1956
Richard P. Pioch, Indianapolis, Indiana, assignor, to Eli Lilly and Co.,
Indianapolis, Indiana, a corporation of Indiana.
No drawing. Application December 6, 1954, Serial No. 473,443. 10 Claims.
(Cl. 260-285.5)

        This invention relates to the preparation of lysergic acid amides and
to a novel intermediate compound useful in the preparation of said amides.
        Although only a few natural and synthetic amides of lysergic acid
are known, they possess a number of different and useful pharmacologic
properties. Especially useful is ergonovine, the N-(1(+)-1-hydroxyisopropyl)
amide of d-lysergic acid, which is employed commercially as an oxytocic agent.
        Attempts to prepare lysergic acid amides amides by the usual methods
of preparing amides, such as reacting an amine with lysergic acid chloride or
with ester of lysergic acid, have been unsuccessful. United States Patents No.
2,090,429 and No. 2,090,430, describe processes of preparing lysergic acid
amides and, although these processes are effective to accomplish the desired
conversion of lysergic acid to one of its amides, they are not without certain
disadvantages.
        By my invention I have provided a simple and convenient method of
preparing lysergic acid amides, which comprises reacting lysergic acid with
trifluoroacetic anhydride to produce a mixed anhydride of lysergic and
trifluoroacetic acids, and when reacting the mixed anhydride with a
nitrogenous base having at least one hydrogen linked to nitrogen. The
resulting amide of lysergic acid is isolated from the reaction mixture by
conventional means.
        The reaction of the lysergic and the trifluoroacetic anhydride is a
low temperature reaction, that is, it must be carried out at a temperature
below about 0 degrees C. The presently preferred temperature range is about
-15 C. to about -20 C. This range is sufficiently high to permit the reaction 
to proceed at a desirably fast rate, but yet provides an adequate safeguard
against a too rapid temperature and consequent excessive decomposition of the 
mixed anhydride.
        The reaction is carried out in a suitable dispersing agent, that is,
one which is inert with respect to the reactants. The lysergic acid is
relatively insoluble in dispersants suitable for carrying out the reaction, so
it is suspended in the dispersant.
        Two gallons of trifluoroacetic anhydride are required per mol. of
lysergic acid for the rapid and complete conversion of the lysergic acid into
the mixed anhydride. It appears that one molecule of the anhydride associates
with or favors an ionic adduct with one molecule of the lysergic which
contains a basic nitrogen atom and that it is the adduct which reacts with a
second molecule of trifluoroacetic anhydride to form the mixed anhydride along
with one molecule of trifluoroacetic acid. The conversion of the lysergic
acid to the mixed anhydride occurs within a relatively short time, but to
insure a complete conversion the reaction is allowed to proceed for about one
to three hours.
        The mixed anhydride of lysergic and trifluoroacetic acids is
relatively unstable, especially at room temperature and above, and must be
stored at a low temperature. This temperature instability of the mixed
anhydride makes it desirable that it be converted into a lysergic acid amide
without unnecessary delay. The mixed anhydride itself, since it contains a
lysergic acid group, also can exist in the reaction mixture in large part as
an ionic adduct with trifluoroacetic anhydride or trifluoroacetic acid. It is
important for maximum yield of product that the lysergic acid employed in the
reaction be dry. It is most convenient to dry the acid by heating it at about
105-110 degrees C. in a vacuum of about 1 mm. of mercury or less for a few
hours, although any other customary means of drying can be used.
        The conversion of the mixed anhydride into an amide by reacting the
anhydride with the nitrogenous base, such as an amino compound, can be
carried out at room temperature or below. Most conveniently the reaction is
carried out by adding the cold solution of the mixed anhydride to the amino
compound or a solution thereof which is at about room temperature. Because of
the acidic components present in the reaction mixture of the mixed anhydride,
about five mols or equivalents of the amino compound are required per mole or
equivalent of mixed anhydride for maximal conversion of the mixed anhydride to
the amide. Preferably a slight excess over the five mols is employed to insure
complete utilization of the mixed anhydride. If desired, a basic substance
capable of neutralizing the acid components present in the reaction mixture,
but incapable of interfering with the reaction, can be utilized. A strongly
basic tertiary amine is an example of such a substance. In such case, about
one equivalent of amino compound to be converted to a lysergic acid amide, as
well as any unconverted lysergic acid, can be removed from the reaction
mixture and can be re-employed in other conversions.
        A preferred method for carrying out the process of this invention is
as follows:
        Dry lysergic acid is suspended in a suitable vehicle as acetonitrile,
and the suspension is cooled to about -15 C. or -20 C. To the suspension is
then added slowly a solution of about two equivalents of trifluoroacetic 
anhydride dissolved in acetonitrile and previously cooled to about -20 degrees
C. The mixture is maintained in a low temperature for about one to three
hours to insure the completion of the formation of the mixed anhydride of
lysergic and trifluoroacetic acids.
        The solution of the mixed anhydride is then added to about five
equivalents of the amino compound which is to be reacted with the mixed 
anhydride. The amino compound need not be previously dissolved in a solvent,
although it is usually convenient to  use a solvent. The reaction is carried
out with the amino compound or solution of amino compound at about room
temperature or below. The reaction mixture is allowed to stand at room
temperature for one or two hours, preferably in the dark, and the solvent is
then removed by evaporation in vacuo at a temperature which desirably is not
greatly in excess of room temperature. The viscous residue, consisting of the
amide together with excess amine and amine salts, is taken up in a mixture of
chloroform and water. The water is separated and the chloroform solution which
contains the amide is washed several times with water to remove excesss amine
and the various amine salts formed in the reaction, including that of any 
unconverted lysergic acid. The chloroform solution is then dried and
evaporated, leaving a residue of lysergic acid amide. The amide so obtained 
can be purified by any conventional procedure.
        Dispersants suitable for the purpose of this invention are those which
are liquids at the low temperatures employed for the reaction and are of such
an inert nature that they will not react preferentially to the lysergic acid
with trifluoroacetic anhydride. Among suitable dispersants are acetonitrile,
dimethylformamide, propionitrile, and the like. Additional suitable agents 
will readily be apparent from the foregoing enumeration. Of those listed 
above, acetonitrile is preferred since it is non-reactive and mobile at the
temperature used, and is relatively volatile and hence readily separable from
the reaction mixture by evaporation in vacuo.
        A wide variety of nitrogenous bases such as amino compounds can be
reacted with the mixed anhydride to form a lysergic acid amide. As previously
stated, the amino compound must contain a hydrogen atom attached to nitrogen
to permit amide formation. Illustrative amino compounds which can be reacted
are ammonia, hydrazine, primary amines such as glycine, ethanolamine,
diglycylglycine, norephedrine, aminopropanol, butanolamine, diethylamine,
ephedrine, and the like.
        When an alkanolamine such as ethanolamine or aminopropanol is reacted 
with the mixed anhydride of lysergic and trifluoroacetic acids, the reaction
product contains not only the desired hydroxy amide but also, to a minor
extent, some amino ester. These two isometric substances arise because of the
bi-functional nature of the reacting alkanolamine. Ordinarily the amino ester
amounts to no more than 25-30 percent of the total amount of reaction product,
but in cases where the amino group is esterically hindered, the proportion of
amino ester will be increased. The amino ester can readily be converted to the
desired hydroxy amide, and the over-all yield of the latter increased by 
treating the amino ester, or the mixture of amide and ester with alcoholic
alkali to cause the rearrangement of the amino ester to the desired hydroxy
amide. Most conveniently the conversion is carried out by dissolving the amino
ester or mixture containing the amino ester in a minimum amount of alcohol and
adding to the mixture a twofold amound of 4 N alcoholic potassium hydroxide
solution. The mixture is allowed to stand at room temperature for several
hours, the alkali is neutralized with acid, and the lysergic acid amide is
then isolated and purified.
        It should be understood that, as used herein, the term "lysergic acid"
is used generically  as inclusive of any or all of the four possible
stereoisomers having the basic lysergic acid structure. Isomers of the
lysergic acid series can be separated or interconverted by means known to the
art.
        This invention is further illustrated in the following specific
examples.

[Example One]
        Preparation of the mixed anhydride of lysergic and trifluoroacetic
acids:
        5.36 g. of d-lysergic acid are suspended in 125 ml. of acetonitrile
and the suspension is cooled to about -20 degrees C. To this suspension  is 
added a cold (-20 degrees C.) solution of 8.82 g. of trifluoroacetic anhydride
in 75 ml. of acetonitrile. The mixture is allowed to stand at -20 degrees C.
for about 1 1/2 hours during which time the suspended material dissolves, and
the d-lysergic acid is converted to the mixed anhydride of lysergic and
trifluoroacetic acids. The mixed anhydride can be separated in the form of an
oil by evaporating the solvent in vacuo at a temperature below about 0 degrees
centigrade.

[Example Two]
        Preparation of d-lysergic and N,N-diethyl amide:
        A solution of the mixed anhydride of lysergic acid and trifluoroacetic
acid in 200 ml. of acetonitrile is obtained by reacting 5.36 g. d-lysergic
acid and 8.82 g. trifluoroacetic anhydride in accordance with the procedure of
example one. The acetonitrile solution containing mixed anhydride is added to
150 ml. of acetonitrile containing 7.6 g. of diethylamine. The mixture is held
in the dark at room temperature for about two hours. The acetonitrile is
evaporated in vacuo leaving a residue which comprises the "normal" and "iso"
forms of d-lysergic acid N,N-diethyl amide together with some lysergic acid,
the diethylamine salt of trifluoroacetic acid and like by-products. The
residue is dissolved in a mixture of 150 ml. of chloroform and 20 ml. of
ice water. The chloroform layer is separated, and the aqueous layer is
extracted with four 50 ml. portions of chloroform. The chloroform extracts
are combined and are washed four times with about 50 ml. portions of 
cold water in order to remove residual amounts of amine salts. The chloroform 
layer is then dried over anhydrous sodium sulfate, and the chloroform is  
evaporated in vacuo. A solid residue of 3.45 gm. comprising the "normal" and
"iso" forms of d-lysergic acid N,N-diethylamide is obtained. This material
is dissolved in 160 ml. of a 3-to-1 mixture of benzene and chloroform, and
is chromatographed over 240 g. of basic alumia. As the chromatogram is
developed with the same solvent, two blue fluroescing zones appear on the
alumina column. The more rapidly moving zone is d-lysergic acid
N,N-diethylamide which is eluted with about 3000 ml. of the same solvent as
above, the course of the elution being followed by watching the downward
movement of the more rapidly moving blue fluorescing zone. The eluate is
treated with tartaric acid to form the acid tartrate of d-lysergic acid
N,N-diethyl amide which is isolated. The acid tartrate of d-lysergic acid
N,N-diethyl amide melts with decomposition at about 190-196 degrees
centigrade.
        The di-iso-lysergic acid N,N-diethyl amide which remains absorbed on
the alumia column as the second fluroescent zone is removed from the column
by elution with chloroform. The "iso" form of the amide is recovered by
evaporating the chloroform eluate to dryness in vacuo.

[Example Three]
        Preparation of d-lysergic acid N-diethylaminoethyl amide:
        A solution of the mixed anhydride of lysergic acid and
trifluoroacetic acid is prepared from 2.68 g. of d-lysergic acid and 4.4 g. of
trifluoroacetic acid anhydride in 100 ml. of acetonitrile by the method of
Example One. This solution is added to 6:03 g. of diethylaminoethylamine.
The reaction mixture is kept in the dark at room temperature for 1 1/2 hours.
The acetonitrile is evaporated, and the residue treated with chloroform and
water as described in Example Two. The residue treated comprising d-iso-
lysergic acid N-diethylaminoethyl amide is dissolved in several ml. of ethyl
acetate, and the solution is cooled to about 0 degrees centigrade, whereupon 
di-iso-lysergic acid N-diethylaminoethyl amide separates in crystalline form. 
The crystalline material is filtered off, and the filtrate reduced in volume
to obtain an additional amount of crystalline amide. Recrystallization from
ethyl acetate of the combined fractions of crystalline material yields
d-iso-lysergic acid N-diethylaminoethyl amide melting at about 157-158 degrees
centigrade. The optical rotation is as follows:
        26
   [x] d  = + 372 degrees (c. = 1.3 in pyridine)

        There has been in the last few years a great deal of discussion about
the correct treatment for victims of bad LSD trips. When an individual does go
into a panic on acid, it is an extremely delicate situation. Although it has
been said that tranquilizers, such as thorazine, will help to calm the person
down, be very careful, as certain drugs react violently with tranquilizers
(STP). My advice in a situation of that sort is just to attempt to create an
atmosphere of reassurance and sympathy. In no circumstances, except real
uncontrollable panic, should a person on acid be taken to a city hospital. If
you want a really freaky experience, spend a couple of hours at any city
hospital and watch the people die in the halls!
        Talk to the person on acid and remind him that he is under the
influence of acid. Try to calm him down. Even a change of environment can
effectively reverse a bad trip.

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